Charcot-Marie-Tooth disease dominant intermediate E (CMTDIE) is a dominantly inherited peripheral neuropathy caused by heterozygous variants in INF2, the gene encoding inverted formin 2. It is the neurological arm of a two-organ disorder: the same gene, and often the same variant, also causes autosomal dominant focal segmental glomerulosclerosis (FSGS), and the combined neuropathy-plus-nephropathy presentation is what led to INF2 being tested in CMT at all. The organising fact of this entry is that the disease mutations are not scattered across the gene. Every pathogenic INF2 allele reported to date lies in the amino-terminal region, and in the CMT-plus-FSGS series all of them fell in exons 2 and 3, which encode the diaphanous inhibitory domain (DID). That domain is regulatory rather than catalytic, so the natural reading is that these variants change how INF2 is controlled rather than what it can do. Biochemistry has since made that reading concrete, and in a way that inverts the intuitive model. Purified INF2 is not autoinhibited - it polymerises actin constitutively in vitro - so the DID cannot be holding the molecule shut on its own. The missing inhibitor was purified from brain as a complex of cyclase-associated protein with lysine-acetylated actin, which requires the DID to act, and disease-associated INF2 mutants are poorly inhibited by it. So the DID variants are best understood as escaping an externally supplied brake, not as destroying a function. That is why this entry tags the actin-assembly node GAIN_OF_FUNCTION rather than INCREASED: the claim is that the process has left normal regulatory control, not that it is merely running faster. That reading is not only biochemical any more. In mice, a disease-associated INF2 point mutation confers susceptibility to glomerular disease while the knockout does not - which is the experiment that separates gain of function from haploinsufficiency in vivo rather than in a tube. How the same lesion reaches two tissues is partly answered, and the answer is positional. Variants between residues 184 and 245 give monogenic FSGS; variants between residues 57 and 184 give the dual CMT-plus-FSGS disease, and the dual-phenotype variants cause more mitochondrial fragmentation and more cytoskeletal disruption in cells. So this entity is the more globally disruptive end of one gradient rather than a separate mechanism. INF2 is strongly expressed in both Schwann-cell cytoplasm and podocytes; in Schwann cells it colocalises and interacts with MAL, and mutant INF2 perturbs the INF2-MAL-CDC42 pathway, disorganises the cytoskeleton, binds CDC42 more avidly and mislocalises all three proteins. Nerve biopsy in six patients reads the result as a global disorder of the Schwann cell actin cytoskeleton with abnormal cytoplasmic actin accumulation - the first peripheral nerve disorder described as a Schwann cell actinopathy. What the positional rule does not explain is the intrafamilial variability, and the entry keeps that open. One CMT-range allele segregated as isolated FSGS in some members of a family and as the dual phenotype in others, so position sets what an allele can do and something unidentified decides what it does. Separately, a three-generation family with a cryptic splicing allele had unambiguous intermediate CMT with normal albumin and creatinine and at most mildly raised urine protein, so kidney involvement is common but not obligate - and the practical consequence, stated by those authors, is that INF2 testing should not be reserved for patients who have both. A second family shows the converse trap: INF2 renal disease is not always FSGS on biopsy. Where the genotype changes management is transplantation. Genetic FSGS generally does not recur in the graft, and four transplants in one INF2 family were recurrence-free. Electrophysiologically the neuropathy is intermediate: nerve conduction studies show demyelinating and axonal features together, which is what places this entity in the dominant intermediate CMT group rather than with CMT1 or CMT2. Nerve pathology matches, with heavy loss of myelinated fibres, onion bulbs and regeneration clusters, plus a distinctive ultrastructural finding in the non-myelinating compartment: supernumerary elongated Schwann cell extensions around unmyelinated fibres.
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name: Charcot-Marie-Tooth Disease Dominant Intermediate E
category: Mendelian
creation_date: "2026-09-03T19:00:00Z"
synonyms:
- CMTDIE
- CMT dominant intermediate E
- DI-CMTE
- INF2-related Charcot-Marie-Tooth disease
- Charcot-Marie-Tooth neuropathy with focal segmental glomerulosclerosis
description: >-
Charcot-Marie-Tooth disease dominant intermediate E (CMTDIE) is a dominantly inherited
peripheral neuropathy caused by heterozygous variants in INF2, the gene encoding inverted
formin 2. It is the neurological arm of a two-organ disorder: the same gene, and often the
same variant, also causes autosomal dominant focal segmental glomerulosclerosis (FSGS), and
the combined neuropathy-plus-nephropathy presentation is what led to INF2 being tested in
CMT at all.
The organising fact of this entry is that the disease mutations are not scattered across the
gene. Every pathogenic INF2 allele reported to date lies in the amino-terminal region, and
in the CMT-plus-FSGS series all of them fell in exons 2 and 3, which encode the diaphanous
inhibitory domain (DID). That domain is regulatory rather than catalytic, so the natural
reading is that these variants change how INF2 is controlled rather than what it can do.
Biochemistry has since made that reading concrete, and in a way that inverts the intuitive
model. Purified INF2 is not autoinhibited - it polymerises actin constitutively in vitro -
so the DID cannot be holding the molecule shut on its own. The missing inhibitor was
purified from brain as a complex of cyclase-associated protein with lysine-acetylated actin,
which requires the DID to act, and disease-associated INF2 mutants are poorly inhibited by
it. So the DID variants are best understood as escaping an externally supplied brake, not as
destroying a function. That is why this entry tags the actin-assembly node GAIN_OF_FUNCTION
rather than INCREASED: the claim is that the process has left normal regulatory control, not
that it is merely running faster.
That reading is not only biochemical any more. In mice, a disease-associated INF2 point
mutation confers susceptibility to glomerular disease while the knockout does not - which is
the experiment that separates gain of function from haploinsufficiency in vivo rather than in
a tube.
How the same lesion reaches two tissues is partly answered, and the answer is positional.
Variants between residues 184 and 245 give monogenic FSGS; variants between residues 57 and
184 give the dual CMT-plus-FSGS disease, and the dual-phenotype variants cause more
mitochondrial fragmentation and more cytoskeletal disruption in cells. So this entity is the
more globally disruptive end of one gradient rather than a separate mechanism. INF2 is
strongly expressed in both Schwann-cell cytoplasm and podocytes; in Schwann cells it
colocalises and interacts with MAL, and mutant INF2 perturbs the INF2-MAL-CDC42 pathway,
disorganises the cytoskeleton, binds CDC42 more avidly and mislocalises all three proteins.
Nerve biopsy in six patients reads the result as a global disorder of the Schwann cell actin
cytoskeleton with abnormal cytoplasmic actin accumulation - the first peripheral nerve
disorder described as a Schwann cell actinopathy.
What the positional rule does not explain is the intrafamilial variability, and the entry
keeps that open. One CMT-range allele segregated as isolated FSGS in some members of a family
and as the dual phenotype in others, so position sets what an allele can do and something
unidentified decides what it does. Separately, a three-generation family with a cryptic
splicing allele had unambiguous intermediate CMT with normal albumin and creatinine and at
most mildly raised urine protein, so kidney involvement is common but not obligate - and the
practical consequence, stated by those authors, is that INF2 testing should not be reserved
for patients who have both. A second family shows the converse trap: INF2 renal disease is
not always FSGS on biopsy.
Where the genotype changes management is transplantation. Genetic FSGS generally does not
recur in the graft, and four transplants in one INF2 family were recurrence-free.
Electrophysiologically the neuropathy is intermediate: nerve conduction studies show
demyelinating and axonal features together, which is what places this entity in the dominant
intermediate CMT group rather than with CMT1 or CMT2. Nerve pathology matches, with heavy
loss of myelinated fibres, onion bulbs and regeneration clusters, plus a distinctive
ultrastructural finding in the non-myelinating compartment: supernumerary elongated Schwann
cell extensions around unmyelinated fibres.
disease_term:
preferred_term: Charcot-Marie-Tooth disease dominant intermediate E
term:
id: MONDO:0013758
label: Charcot-Marie-Tooth disease dominant intermediate E
parents:
- Charcot-Marie-Tooth Disease
- Peripheral Neuropathy
inheritance:
- name: Autosomal dominant
description: >-
Heterozygous INF2 variants. The founding series identified nine new heterozygous mutations
in 12 of 16 index patients with CMT and FSGS, and the later cryptic-splicing family shows
dominant transmission across three generations. Expressivity is variable even within a
single family: the same allele has produced isolated FSGS in some relatives and combined
FSGS with neuropathy in others.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
expressivity: VARIABLE
evidence:
- reference: PMID:22187985
reference_title: "INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified nine new heterozygous mutations in 12 of the 16 index patients (75%), all located in exons 2 and 3, encoding the diaphanous-inhibitory domain of INF2."
explanation: >-
Heterozygous state in every index patient, which is the dominant pattern, and the
restriction of the alleles to the DID-encoding exons.
- reference: PMID:25943269
reference_title: "INF2 mutations associated with dominant inherited intermediate Charcot-Marie-Tooth neuropathy with focal segmental glomerulosclerosis in two Chinese patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Intrafamilial variability can be found with the same INF2 mutation."
explanation: >-
Direct statement of variable expressivity, which is why penetrance of the renal arm
cannot be read off the genotype.
pathophysiology:
- name: INF2 Diaphanous-Inhibitory-Domain Variant
biological_scale: MOLECULAR
description: >-
A heterozygous variant in the amino-terminal region of INF2. In the founding CMT-plus-FSGS
series every allele lay in exons 2 and 3, which encode the diaphanous inhibitory domain,
and a systematic review of the whole pathogenic allele set a decade later reached the same
conclusion for INF2 disease as a whole. Missense substitutions dominate, but the spectrum
also includes a cryptic splicing allele (c.271C>G, p.Arg91Gly) whose real consequence is
an in-frame 40-amino-acid deletion inside the same domain.
genes:
- preferred_term: INF2
term:
id: hgnc:23791
label: INF2
genetic_context:
allele_type: missense, and one cryptic splice allele producing an in-frame 40-residue deletion
variant_origin: GERMLINE
zygosity: HETEROZYGOUS
functional_impact_category: GAIN_OF_FUNCTION
description: >-
Categorised as gain of function on two independent lines: disease-associated INF2 mutants
escape inhibition by the CAP-KAc-actin complex in vitro, and in mice a disease point
mutation confers susceptibility to glomerular disease where the knockout does not.
The two lines differ in allele coverage. The biochemistry tested both ranges - R218Q, an
FSGS allele, and L77R, which the source calls a CMTD mutant and which sits at residue 77,
inside the 57-184 CMT-associated span this entry describes - and found reduced
CAP-KAc-actin inhibition of both, so that line bears on CMT alleles directly. The mouse
work uses R218Q alone, so it is the in vivo line whose inference to CMT-range alleles is
stated rather than assumed. It is drawn here and not for
the nephrin route because the two claims have different scopes. Gain versus loss of
function is a property of the *domain*: every pathogenic INF2 allele sits in the DID, the
biochemical escape from CAP-KAc-actin inhibition was measured across disease mutants
rather than on one, and the knockout-versus-point-mutant comparison tests the class of
mechanism, not a residue. The nephrin route is the opposite - a specific molecular
pathway, in one cell type, demonstrated for one allele - so it stays allele-local. Every
evidence item on both is graded INDIRECT regardless.
downstream:
- target: Loss of Facilitated Autoinhibition of INF2
causal_link_type: DIRECT
evidence:
- reference: PMID:22187985
reference_title: "INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified nine new heterozygous mutations in 12 of the 16 index patients (75%), all located in exons 2 and 3, encoding the diaphanous-inhibitory domain of INF2."
explanation: The founding allelic series and its confinement to the regulatory domain.
- reference: PMID:32451589
reference_title: "The formin INF2 in disease: progress from 10 years of research."
supports: SUPPORT
evidence_source: OTHER
snippet: "All known INF2 gene mutations causing disease map to the exons encoding the amino-terminal domain."
explanation: >-
A systematic exon-by-exon review confirming the localisation across the whole reported
mutation set, not just the founding cohort.
- reference: PMID:30680856
reference_title: "A cryptic splicing mutation in the INF2 gene causing Charcot-Marie-Tooth disease with minimal glomerular dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Genetic analysis found a c.271C > G (p. Arg91Gly) variation in INF2 exon 2, and in vitro splicing assays showed the deletion of the last 120 nucleotides of INF2 exon 2 leading to a 40 amino acids in-frame deletion (p. Arg91_p. Gln130del)."
explanation: >-
The splicing allele, which is why the allele spectrum cannot be described as purely
missense.
- reference: PMID:39536114
reference_title: "INF2 mutations cause kidney disease through a gain-of-function mechanism."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "Despite established roles in multiple cellular processes, neither INF2 knockout mice nor mice with a disease-associated point mutation display an evident kidney or neurologic phenotype."
explanation: >-
The baseline observation that makes the comparison below meaningful: unchallenged, both
genotypes look normal, so the gain-of-function claim rests on the challenge experiment
rather than on a spontaneous phenotype. Graded INDIRECT for the same reason as the nephrin
node - the point mutation modelled is R218Q, an FSGS-range allele.
- reference: PMID:39536114
reference_title: "INF2 mutations cause kidney disease through a gain-of-function mechanism."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "R218Q INF2 mice are susceptible to glomerular disease, in contrast to INF2 knockout mice."
explanation: >-
The in vivo discrimination between gain and loss of function: the point-mutant mouse is
susceptible where the knockout is not. The allele is R218Q, an FSGS-range variant, so the
item is graded INDIRECT for a CMT entry; see genetic_context for why this entry treats the
gain-of-function conclusion as generalising across the DID while the nephrin route does
not.
- name: Loss of Facilitated Autoinhibition of INF2
biological_scale: MOLECULAR
description: >-
Wild-type INF2 is not autoinhibited when purified; it accelerates actin polymerisation
from monomers as efficiently as a construct lacking the DID entirely. The brake is
supplied in trans by a complex of cyclase-associated protein with lysine-acetylated actin,
and that inhibition requires the DID. Disease-associated INF2 mutants are poorly inhibited
by this complex, so a DID variant releases the formin from an externally imposed control
rather than crippling it - which is why this node is tagged GAIN_OF_FUNCTION rather than
INCREASED.
molecular_functions:
- preferred_term: actin binding
term:
id: GO:0003779
label: actin binding
biological_processes:
- preferred_term: actin filament polymerization
modifier: GAIN_OF_FUNCTION
term:
id: GO:0030041
label: actin filament polymerization
downstream:
- target: Disruption of the INF2-MAL-CDC42 Pathway in Schwann Cells
causal_link_type: DIRECT
- target: Podocyte Actin Cytoskeleton Disorganization
causal_link_type: DIRECT
evidence:
- reference: PMID:30962575
reference_title: "A complex containing lysine-acetylated actin inhibits the formin INF2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Interestingly, purified INF2 is not autoinhibited, suggesting the existence of other cellular inhibitors."
explanation: >-
Establishes that the DID does not act as a conventional intramolecular brake, which is
the premise the rest of the node rests on.
- reference: PMID:30962575
reference_title: "A complex containing lysine-acetylated actin inhibits the formin INF2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Inhibition of INF2 by CAP-KAc-actin is dependent on the INF2 diaphanous inhibitory domain (DID)."
explanation: >-
Links the inhibitory mechanism to the exact domain in which every disease allele sits.
- reference: PMID:30962575
reference_title: "A complex containing lysine-acetylated actin inhibits the formin INF2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Disease-associated INF2 mutants are poorly inhibited by CAP-KAc-actin, suggesting that focal segmental glomerulosclerosis and Charcot-Marie-Tooth disease result from reduced CAP-KAc-actin binding."
explanation: >-
The mechanistic claim itself, tested on the disease alleles rather than on a designed
DID mutant.
- reference: PMID:30962575
reference_title: "A complex containing lysine-acetylated actin inhibits the formin INF2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We therefore asked whether CAP/actin could inhibit two INF2 mutants: R218Q, a common FSGS mutant22; and L77R, a CMTD mutant23."
explanation: >-
Names the two alleles the biochemistry was run on. L77R is called a CMTD mutant by the
source and sits at residue 77, inside the 57-184 CMT-associated span, so the escape from
CAP-KAc-actin inhibition is not measured only on FSGS alleles. The trailing digits are the
source's superscript citation markers, carried through by the cache.
- reference: PMID:30962575
reference_title: "A complex containing lysine-acetylated actin inhibits the formin INF2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "CAP/CSKA displays reduced inhibition of both mutants biochemically, with R218Q being particularly resistant"
explanation: >-
The result for that pair. Both alleles escape inhibition, so the CMT allele carries the
mechanism too; the FSGS allele is the more resistant of the two, which is a quantitative
difference and not a difference in kind.
- name: Disruption of the INF2-MAL-CDC42 Pathway in Schwann Cells
biological_scale: CELLULAR
description: >-
INF2 is strongly expressed in Schwann-cell cytoplasm, where it colocalises and interacts
with myelin and lymphocyte protein (MAL) and engages the Rho-family GTPase CDC42 - both of
them proteins implicated in myelination and myelin maintenance. Mutant INF2 perturbs this
three-way pathway: the cytoskeleton is disorganised, INF2 binding to CDC42 is enhanced,
and INF2, MAL and CDC42 are all mislocalised.
cell_types:
- preferred_term: Schwann cell
term:
id: CL:0002573
label: Schwann cell
biological_processes:
- preferred_term: Rho protein signal transduction
modifier: ABNORMAL
term:
id: GO:0007266
label: Rho protein signal transduction
- preferred_term: regulation of actin cytoskeleton organization
modifier: ABNORMAL
term:
id: GO:0032956
label: regulation of actin cytoskeleton organization
downstream:
- target: Schwann Cell Myelin Maintenance Failure
causal_link_type: DIRECT
evidence:
- reference: PMID:22187985
reference_title: "INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Immunohistochemical analysis revealed strong INF2 expression in Schwann-cell cytoplasm and podocytes."
explanation: >-
Establishes that both affected cell types actually express the protein, which is the
minimum requirement for a shared cell-autonomous mechanism.
- reference: PMID:22187985
reference_title: "INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Moreover, we demonstrated that INF2 colocalizes and interacts with MAL in Schwann cells."
explanation: The physical interaction that makes MAL part of this node rather than a bystander.
- reference: PMID:22187985
reference_title: "INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The INF2 mutants perturbed the INF2-MAL-CDC42 pathway, resulting in cytoskeleton disorganization, enhanced INF2 binding to CDC42 and mislocalization of INF2, MAL, and CDC42."
explanation: >-
The functional consequence measured on the patient alleles: enhanced CDC42 binding is
the observation that argues against a simple loss of INF2 activity.
- name: Schwann Cell Myelin Maintenance Failure
biological_scale: CELLULAR
description: >-
MAL and CDC42 are implicated in essential steps of myelination and myelin maintenance, so
the pathway disruption above translates into a failure of the Schwann cell to build and
keep a normal myelin sheath. The non-myelinating Schwann cell compartment is affected too,
taking on supernumerary elongated extensions around unmyelinated fibres.
cell_types:
- preferred_term: Schwann cell
term:
id: CL:0002573
label: Schwann cell
biological_processes:
- preferred_term: myelination in peripheral nervous system
modifier: DECREASED
term:
id: GO:0022011
label: myelination in peripheral nervous system
downstream:
- target: Demyelination with Onion Bulbs and Secondary Axonal Loss
causal_link_type: DIRECT
evidence:
- reference: PMID:22187985
reference_title: "INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "INF2 encodes a formin protein that interacts with the Rho-GTPase CDC42 and myelin and lymphocyte protein (MAL) that are implicated in essential steps of myelination and myelin maintenance."
explanation: >-
Attributes the myelination role to the two partners, which is the step that connects the
cytoskeletal lesion to a myelin phenotype.
- reference: PMID:25943269
reference_title: "INF2 mutations associated with dominant inherited intermediate Charcot-Marie-Tooth neuropathy with focal segmental glomerulosclerosis in two Chinese patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ultrastructurally, numerous elongated extensions of Schwann cells of unmyelinated fibers could be seen in both patients."
explanation: >-
Shows the Schwann cell abnormality is not confined to the myelinating compartment, which
is why this node is about the cell rather than about myelin alone.
- name: Demyelination with Onion Bulbs and Secondary Axonal Loss
biological_scale: TISSUE
description: >-
The nerve-level lesion. Sural nerve biopsy shows moderate-to-severe loss of myelinated
fibres with onion bulbs and regeneration clusters, the histological signature of repeated
demyelination and remyelination with axonal dropout. Clinically and electrophysiologically
this reads as an intermediate neuropathy, with demyelinating and axonal features present
together rather than one or the other.
downstream:
- target: Distal Muscle Weakness
causal_link_type: DIRECT
- target: Distal Amyotrophy
causal_link_type: DIRECT
- target: Distal Sensory Impairment
causal_link_type: DIRECT
- target: Decreased Motor Nerve Conduction Velocity
causal_link_type: DIRECT
- target: Onion Bulb Formation
causal_link_type: DIRECT
- target: Pes Cavus
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- target: Kyphoscoliosis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:25943269
reference_title: "INF2 mutations associated with dominant inherited intermediate Charcot-Marie-Tooth neuropathy with focal segmental glomerulosclerosis in two Chinese patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Sural nerve biopsy revealed moderate-to-severe loss of myelinated fibers with union bulbs and regeneration clusters in both patients."
explanation: >-
The nerve pathology. The quoted source prints "union bulbs"; the intended term is onion
bulbs, and the snippet is reproduced exactly as published rather than silently corrected.
- reference: PMID:30680856
reference_title: "A cryptic splicing mutation in the INF2 gene causing Charcot-Marie-Tooth disease with minimal glomerular dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mean age at CMT disease onset was 11.5 years (3-17), and electrophysiological studies showed demyelinating and axonal features consistent with intermediate CMT."
explanation: >-
The mixed electrophysiology that defines the intermediate category, plus age at onset.
- reference: PMID:24487800
reference_title: "Neuropathologic characterization of INF2-related Charcot-Marie-Tooth disease: evidence for a Schwann cell actinopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Pathologic lesions suggested chronic demyelination and remyelination associated with progressive axonal loss."
explanation: >-
The nerve lesion in the only series assembled specifically to characterise CMTDIE
pathology - six patients rather than two - which is the primary source for this node.
- reference: PMID:24487800
reference_title: "Neuropathologic characterization of INF2-related Charcot-Marie-Tooth disease: evidence for a Schwann cell actinopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "By electron microscopy, we observed unusual whorl-like proliferations of flattened Schwann cell cytoplasm and anomalies of unmyelinating Schwann cell cytoplasm with supernumerary elongated extensions similar to those described in CMT4C."
explanation: >-
The ultrastructural findings, including the non-myelinating Schwann cell extensions
independently reported in the Chinese patients above.
- name: Schwann Cell Actinopathy
biological_scale: CELLULAR
description: >-
The nerve-biopsy series draws a stronger conclusion than "demyelination", and it is the
conclusion that ties the peripheral nerve lesion back to the molecular mechanism. Across six
CMTDIE patients the lesions were read as a global disorder of the Schwann cell actin
cytoskeleton, with abnormal cytoplasmic accumulation of the actin isoform itself, making
CMTDIE the first peripheral nerve disorder described as a Schwann cell actinopathy.
cell_types:
- preferred_term: Schwann cell
term:
id: CL:0002573
label: Schwann cell
biological_processes:
- preferred_term: actin filament organization
modifier: ABNORMAL
term:
id: GO:0007015
label: actin filament organization
evidence:
- reference: PMID:24487800
reference_title: "Neuropathologic characterization of INF2-related Charcot-Marie-Tooth disease: evidence for a Schwann cell actinopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our results suggest that these lesions reflect a global disorder of the actin cytoskeleton in Schwann cells and that CMTDIE is the first peripheral nerve disorder associated with a Schwann cell actinopathy."
explanation: >-
The authors' interpretation of their own series, and the reason this is a node rather
than a line in the demyelination node: it is a claim about the cell, not the sheath.
- reference: PMID:24487800
reference_title: "Neuropathologic characterization of INF2-related Charcot-Marie-Tooth disease: evidence for a Schwann cell actinopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We also observed abnormal accumulation of beta-actin in the cytoplasm of Schwann cells."
explanation: >-
The direct observation of accumulated actin in patient nerve, which is the human tissue
counterpart of the de-repressed actin assembly measured biochemically.
notes: >-
This node has no downstream edge of its own. It is a characterisation of the same Schwann
cell lesion that "Schwann Cell Myelin Maintenance Failure" carries into the pathograph, and
duplicating the edge would double-count the chain.
- name: Podocyte Actin Cytoskeleton Disorganization
biological_scale: CELLULAR
description: >-
The second arm. INF2 is strongly expressed in podocytes, whose foot processes are
load-bearing actin structures, and mutant INF2 disorganises the actin cytoskeleton. The
same de-repressed actin assembly that damages the Schwann cell acts here on a cell whose
architecture is actin.
cell_types:
- preferred_term: podocyte
term:
id: CL:0000653
label: podocyte
biological_processes:
- preferred_term: actin filament organization
modifier: ABNORMAL
term:
id: GO:0007015
label: actin filament organization
downstream:
- target: Podocyte Loss and Glomerular Scarring
causal_link_type: DIRECT
evidence:
- reference: PMID:22187985
reference_title: "INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Immunohistochemical analysis revealed strong INF2 expression in Schwann-cell cytoplasm and podocytes."
explanation: Podocyte expression, establishing the renal arm as cell-autonomous.
- reference: PMID:22187985
reference_title: "INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The INF2 mutants perturbed the INF2-MAL-CDC42 pathway, resulting in cytoskeleton disorganization, enhanced INF2 binding to CDC42 and mislocalization of INF2, MAL, and CDC42."
explanation: >-
Cytoskeletal disorganisation is the measured consequence of the mutant protein; it is
cited here as the shared lesion rather than as a podocyte-specific experiment.
notes: >-
The evidence in this node is INDIRECT for the podocyte specifically: the cytoskeletal
disorganisation assay in the founding paper is not reported as podocyte-restricted, and
what ties it to the kidney is INF2 expression plus the established actin dependence of
foot-process architecture rather than a podocyte experiment on these alleles.
- name: Dynein-Mediated Nephrin Mistrafficking and Proteasomal Degradation
biological_scale: MOLECULAR
description: >-
A specific route from the actin lesion to podocyte failure, worked out in detail for the
INF2 R218Q allele. Normally INF2 sequesters dynein light chain 1; the mutant fails to, so
Dynll1 is captured by PI31 and dynein carries the slit-diaphragm protein nephrin to the
proteasome. Knocking down Dynll1 or PI31, inactivating dynein, or inhibiting the proteasome
each restores nephrin, and bortezomib rescues the mouse.
Two things limit how far this can be carried into CMTDIE, and both are recorded here rather
than glossed. R218 lies in the residue range associated with monogenic FSGS, not in the
range associated with the dual CMT/FSGS phenotype, so this is an adjacent allele rather
than a CMTDIE allele. And nephrin is a podocyte protein, so nothing here speaks to the
nerve arm at all.
cell_types:
- preferred_term: podocyte
term:
id: CL:0000653
label: podocyte
biological_processes:
- preferred_term: proteasome-mediated ubiquitin-dependent protein catabolic process
modifier: INCREASED
term:
id: GO:0043161
label: proteasome-mediated ubiquitin-dependent protein catabolic process
downstream:
- target: Podocyte Loss and Glomerular Scarring
causal_link_type: DIRECT
evidence:
- reference: PMID:39621430
reference_title: "Dynll1-PI31 Interaction Enhances Proteolysis Through the Proteasome, Representing a Novel Therapeutic Target for INF2-Related FSGS."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "The R218Q mutation in INF2 disrupted sequestration of Dynll1 by INF2, allowing Dynll1 to be captured by PI31 and promoting dynein-mediated transport of nephrin to the proteasome."
explanation: >-
The mechanism itself. Graded INDIRECT because R218Q is an FSGS-range allele and this
entry is about the CMT-range alleles; the inference that the same route operates in
CMTDIE podocytes is not tested.
- reference: PMID:39621430
reference_title: "Dynll1-PI31 Interaction Enhances Proteolysis Through the Proteasome, Representing a Novel Therapeutic Target for INF2-Related FSGS."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "In R218Q KI mice challenged with puromycin aminonucleoside, dynein-mediated mistrafficking and depletion of nephrin were correlated with increased Dynll1-PI31 interaction; the resulting podocytopathy and FSGS were ameliorated by bortezomib."
explanation: >-
The in vivo rescue, which is what makes the pathway a plausible drug target rather than a
cell-culture observation. Same allele-range caveat.
- name: Podocyte Loss and Glomerular Scarring
biological_scale: TISSUE
description: >-
Progressive podocyte loss produces glomerular dysfunction, seen first as proteinuria with
or without other features of nephrotic syndrome, and the histological pattern of scarring
in localised regions of some but not all glomeruli - focal segmental glomerulosclerosis.
In its advanced stage it reaches end-stage renal disease.
downstream:
- target: Proteinuria
causal_link_type: DIRECT
- target: Focal Segmental Glomerulosclerosis
causal_link_type: DIRECT
- target: Stage 5 Chronic Kidney Disease
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:32451589
reference_title: "The formin INF2 in disease: progress from 10 years of research."
supports: SUPPORT
evidence_source: OTHER
snippet: "Patients with FSGS exhibit a progressive loss of podocytes, which causes glomerular dysfunction, and is initially manifested as proteinuria with or without other signs of nephrotic syndrome"
explanation: >-
The podocyte-loss-to-proteinuria sequence, stated for FSGS generally, in the review that
covers the INF2 form specifically.
- reference: PMID:22187985
reference_title: "INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients presented with an intermediate form of Charcot-Marie-Tooth neuropathy as well as a glomerulopathy with FSGS on kidney biopsy."
explanation: Biopsy-confirmed FSGS in the index patients, not merely proteinuria.
phenotypes:
- name: Distal Muscle Weakness
category: Neuromuscular
description: >-
Length-dependent weakness beginning in the legs, typically in the second decade. In the
two Chinese patients onset was at ages 13 and 17; in the cryptic-splicing family the mean
age at onset was 11.5 years with a range of 3 to 17.
frequency: OBLIGATE
phenotype_term:
preferred_term: Distal muscle weakness
term:
id: HP:0002460
label: Distal muscle weakness
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:25943269
reference_title: "INF2 mutations associated with dominant inherited intermediate Charcot-Marie-Tooth neuropathy with focal segmental glomerulosclerosis in two Chinese patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Case 1 is 27 years old and presented with distal muscle weakness and atrophy of legs at the age of 13 and renal failure at the age of 26."
explanation: Distal weakness as the presenting neurological feature, with age at onset.
- reference: PMID:30680856
reference_title: "A cryptic splicing mutation in the INF2 gene causing Charcot-Marie-Tooth disease with minimal glomerular dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mean age at CMT disease onset was 11.5 years (3-17), and electrophysiological studies showed demyelinating and axonal features consistent with intermediate CMT."
explanation: >-
Age at onset in an independent family, quoted here for the onset figure rather than the
electrophysiology.
- name: Distal Amyotrophy
category: Neuromuscular
description: >-
Wasting of the distal leg musculature accompanying the weakness, described in both Chinese
patients as atrophy of the legs.
frequency: FREQUENT
phenotype_term:
preferred_term: Distal amyotrophy
term:
id: HP:0003693
label: Distal amyotrophy
evidence:
- reference: PMID:25943269
reference_title: "INF2 mutations associated with dominant inherited intermediate Charcot-Marie-Tooth neuropathy with focal segmental glomerulosclerosis in two Chinese patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Case 2 is 22 years old and presented with distal muscle weakness and atrophy of the legs with transient attacks of difficulty in speaking at age 17."
explanation: Distal atrophy in the second patient, quoted separately from the first.
notes: >-
FREQUENT rather than OBLIGATE: atrophy is documented in the two patients whose examination
findings are reported in detail, and no series states whether every affected individual
has it.
- name: Distal Sensory Impairment
category: Neurological
description: >-
The neuropathy is sensorimotor rather than purely motor. The three-generation family is
described as having a slowly progressive sensorimotor polyneuropathy.
frequency: FREQUENT
phenotype_term:
preferred_term: Distal sensory impairment
term:
id: HP:0002936
label: Distal sensory impairment
evidence:
- reference: PMID:30680856
reference_title: "A cryptic splicing mutation in the INF2 gene causing Charcot-Marie-Tooth disease with minimal glomerular dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Three males and one female with a mean age of 51 years (26-87) presented with a slowly progressive sensorimotor polyneuropathy, pes cavus, and kyphoscoliosis."
explanation: >-
"Sensorimotor" establishes sensory involvement; the abstract does not give a distal
gradient explicitly, but a length-dependent distribution is what polyneuropathy denotes
in this context.
notes: >-
The cited source says sensorimotor polyneuropathy without describing the sensory
distribution. The distal qualifier in the bound HP term is the standard reading of
polyneuropathy in CMT and not a separate claim from the source.
- name: Decreased Motor Nerve Conduction Velocity
category: Neurophysiological
description: >-
Nerve conduction studies show demyelinating features alongside axonal ones, which is the
definition of the intermediate category and the reason this disorder sits in dominant
intermediate CMT rather than in CMT1 or CMT2.
frequency: FREQUENT
phenotype_term:
preferred_term: Decreased motor nerve conduction velocity
term:
id: HP:0003431
label: Decreased motor nerve conduction velocity
evidence:
- reference: PMID:24487800
reference_title: "Neuropathologic characterization of INF2-related Charcot-Marie-Tooth disease: evidence for a Schwann cell actinopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Motor median nerve conduction velocities were in the range of intermediate CMT disease."
explanation: >-
A reported conduction-velocity finding in a named nerve across six patients, which is why
this phenotype is no longer graded as an inference from the disease's classification.
- reference: PMID:30680856
reference_title: "A cryptic splicing mutation in the INF2 gene causing Charcot-Marie-Tooth disease with minimal glomerular dysfunction."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Mean age at CMT disease onset was 11.5 years (3-17), and electrophysiological studies showed demyelinating and axonal features consistent with intermediate CMT."
explanation: >-
Kept and graded INDIRECT: it reports demyelinating features and an intermediate
classification without giving velocities, so on its own it supports the claim only
through the classification.
notes: >-
Neither source gives a numeric velocity in m/s. What the first one does give is a
measurement in a named nerve reported as falling in the intermediate range, which is a
reported finding rather than a deduction from the disease label - the reason the primary
evidence item here is not marked INDIRECT while the second still is.
- name: Onion Bulb Formation
category: Histopathological
description: >-
Sural nerve biopsy shows onion bulbs together with regeneration clusters on a background
of moderate-to-severe myelinated fibre loss, the signature of repeated demyelination and
remyelination.
frequency: FREQUENT
phenotype_term:
preferred_term: Onion bulb formation
term:
id: HP:0003383
label: Onion bulb formation
evidence:
- reference: PMID:25943269
reference_title: "INF2 mutations associated with dominant inherited intermediate Charcot-Marie-Tooth neuropathy with focal segmental glomerulosclerosis in two Chinese patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Sural nerve biopsy revealed moderate-to-severe loss of myelinated fibers with union bulbs and regeneration clusters in both patients."
explanation: >-
Biopsy finding in both patients. The published text reads "union bulbs"; the snippet
reproduces the source exactly rather than correcting it to onion bulbs.
- name: Pes Cavus
category: Skeletal
description: >-
The classical CMT foot deformity, present in the three-generation family with the cryptic
splicing allele.
frequency: FREQUENT
phenotype_term:
preferred_term: Pes cavus
term:
id: HP:0001761
label: Pes cavus
evidence:
- reference: PMID:30680856
reference_title: "A cryptic splicing mutation in the INF2 gene causing Charcot-Marie-Tooth disease with minimal glomerular dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Three males and one female with a mean age of 51 years (26-87) presented with a slowly progressive sensorimotor polyneuropathy, pes cavus, and kyphoscoliosis."
explanation: Pes cavus in all four affected members of the reported family.
- name: Kyphoscoliosis
category: Skeletal
description: >-
Spinal deformity reported alongside the neuropathy in the cryptic-splicing family.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Kyphoscoliosis
term:
id: HP:0002751
label: Kyphoscoliosis
evidence:
- reference: PMID:30680856
reference_title: "A cryptic splicing mutation in the INF2 gene causing Charcot-Marie-Tooth disease with minimal glomerular dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Three males and one female with a mean age of 51 years (26-87) presented with a slowly progressive sensorimotor polyneuropathy, pes cavus, and kyphoscoliosis."
explanation: >-
Kyphoscoliosis in the one family that reports it. Marked OCCASIONAL because no other
cited series mentions spinal deformity at all.
- name: Proteinuria
category: Renal
description: >-
The earliest renal sign, and the one that varies most across the disorder. It ranges from
frank proteinuria found on routine urinalysis to values only mildly above the reference
range in a family whose albumin and creatinine were normal throughout.
frequency: FREQUENT
phenotype_term:
preferred_term: Proteinuria
term:
id: HP:0000093
label: Proteinuria
evidence:
- reference: PMID:25943269
reference_title: "INF2 mutations associated with dominant inherited intermediate Charcot-Marie-Tooth neuropathy with focal segmental glomerulosclerosis in two Chinese patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Proteinuria was found by routine urine test at the same time."
explanation: Proteinuria detected incidentally at the time of neurological presentation.
- reference: PMID:30680856
reference_title: "A cryptic splicing mutation in the INF2 gene causing Charcot-Marie-Tooth disease with minimal glomerular dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Plasma albumin and creatinine were normal in all four cases, and urine protein was normal in one case and mildly raised in three patients"
explanation: >-
The quantitative low end of the range, and the observation that one affected individual
had no proteinuria at all - which is what stops this being graded OBLIGATE.
- name: Focal Segmental Glomerulosclerosis
category: Renal
description: >-
Biopsy-proven segmental scarring of some but not all glomeruli. It was present in the
index patients of the founding series by definition of their ascertainment, so its
frequency in unselected INF2 neuropathy carriers is not established by that cohort.
frequency: FREQUENT
phenotype_term:
preferred_term: Focal segmental glomerulosclerosis
term:
id: HP:0000097
label: Focal segmental glomerulosclerosis
evidence:
- reference: PMID:22187985
reference_title: "INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients presented with an intermediate form of Charcot-Marie-Tooth neuropathy as well as a glomerulopathy with FSGS on kidney biopsy."
explanation: Histological confirmation rather than inference from proteinuria.
- reference: PMID:30680856
reference_title: "A cryptic splicing mutation in the INF2 gene causing Charcot-Marie-Tooth disease with minimal glomerular dysfunction."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "This report expands the genetic spectrum of INF2-associated disorders and demonstrates that INF2 mutations may provoke isolated CMT with no clinically relevant kidney involvement."
explanation: >-
Recorded as REFUTE against the specific claim that glomerular disease is a constant
feature of this disorder. It does not contradict the founding series, which selected for
patients who had both; it contradicts the generalisation.
- reference: PMID:29038887
reference_title: "Mutations in INF2 may be associated with renal histology other than focal segmental glomerulosclerosis."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "Two patients underwent renal biopsy with the result of minimal-change glomerulopathy and IgA nephropathy respectively."
explanation: >-
Recorded as REFUTE against the claim that INF2 renal disease is always FSGS. In a
14-member INF2 family the two biopsies showed something else entirely, so a non-FSGS
biopsy does not exclude the gene.
notes: >-
The founding cohort was ascertained as CMT *with* FSGS, so it cannot estimate how often
INF2 neuropathy carries renal disease. FREQUENT reflects that, plus one published family
with clinically unimportant kidney findings, plus a second family in which the renal
histology was not FSGS at all.
- name: Stage 5 Chronic Kidney Disease
category: Renal
description: >-
The endpoint of the renal arm when it progresses. One reported patient reached renal
failure at 26, thirteen years after his neurological onset, and three of his relatives
died of renal failure without a recorded neuropathy.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Stage 5 chronic kidney disease
term:
id: HP:0003774
label: Stage 5 chronic kidney disease
evidence:
- reference: PMID:25943269
reference_title: "INF2 mutations associated with dominant inherited intermediate Charcot-Marie-Tooth neuropathy with focal segmental glomerulosclerosis in two Chinese patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Three of his family members died due to pure renal failure."
explanation: >-
Renal failure as a cause of death within one INF2 family, and the phrase "pure renal
failure" is itself the record of relatives who had the kidney arm without the nerve arm.
- reference: PMID:23014460
reference_title: "Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "INF2-related disease showed variable penetrance, with onset of disease ranging widely from childhood to adulthood, and commonly leading to end-stage renal disease in the third and fourth decade of life."
explanation: >-
Timing of renal failure across an INF2 cohort, and the source for calling penetrance
variable. Graded INDIRECT because the cohort is INF2 familial FSGS rather than INF2
neuropathy, so it describes the gene's renal course and not this entry's population.
- reference: PMID:32451589
reference_title: "The formin INF2 in disease: progress from 10 years of research."
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: "the formin INF2 has emerged as an important target of mutations responsible for the appearance of focal segmental glomerulosclerosis, which are histological lesions associated with glomerulus degeneration that often leads to end-stage renal disease"
explanation: >-
Graded INDIRECT: it states the FSGS-to-ESRD progression for INF2-related FSGS in general
rather than measuring it in neuropathy patients.
genetic:
- name: INF2
gene_term:
preferred_term: INF2
term:
id: hgnc:23791
label: INF2
relationship_type: CAUSATIVE
variant_origin: GERMLINE
frequency: >-
Found in 12 of 16 (75%) index patients with Charcot-Marie-Tooth neuropathy plus FSGS who
had already been excluded for PMP22 and MPZ.
features: >-
Pathogenic alleles cluster in the amino-terminal diaphanous inhibitory domain, encoded by
exons 2 and 3 in the founding series.
evidence:
- reference: PMID:22187985
reference_title: "INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We performed direct genotyping of INF2 in 16 index patients with Charcot-Marie-Tooth neuropathy and FSGS who did not have a mutation in PMP22 or MPZ, encoding peripheral myelin protein 22 and myelin protein zero, respectively."
explanation: >-
The denominator and the prior exclusions, which are what make the 75% yield
interpretable.
- reference: PMID:22187985
reference_title: "INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "INF2 mutations appear to cause many cases of FSGS-associated Charcot-Marie-Tooth neuropathy, showing that INF2 is involved in a disease affecting both the kidney glomerulus and the peripheral nervous system."
explanation: The authors' own gene-disease conclusion.
diagnosis:
- name: Nerve conduction studies
description: >-
Motor and sensory conduction studies showing demyelinating and axonal features together,
which places the neuropathy in the intermediate category and narrows the gene panel.
evidence:
- reference: PMID:30680856
reference_title: "A cryptic splicing mutation in the INF2 gene causing Charcot-Marie-Tooth disease with minimal glomerular dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mean age at CMT disease onset was 11.5 years (3-17), and electrophysiological studies showed demyelinating and axonal features consistent with intermediate CMT."
explanation: The electrophysiological pattern used to classify the neuropathy.
- name: INF2 sequencing
description: >-
Targeted sequencing of INF2, concentrating on the amino-terminal exons where every reported
pathogenic allele lies. The cryptic-splicing family is a caution against restricting the
test to patients who have renal disease as well as neuropathy, and against reading a
missense call at face value without a splicing assay.
evidence:
- reference: PMID:30680856
reference_title: "A cryptic splicing mutation in the INF2 gene causing Charcot-Marie-Tooth disease with minimal glomerular dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Consequently, INF2 mutation analysis should not be restricted to individuals with coincident neuropathy and renal disease."
explanation: The authors' explicit testing recommendation.
- reference: PMID:32451589
reference_title: "The formin INF2 in disease: progress from 10 years of research."
supports: SUPPORT
evidence_source: OTHER
snippet: "All known INF2 gene mutations causing disease map to the exons encoding the amino-terminal domain."
explanation: Why the amino-terminal exons are the high-yield target.
- name: Renal biopsy
description: >-
Histological confirmation of focal segmental glomerulosclerosis in a carrier with
proteinuria.
evidence:
- reference: PMID:22187985
reference_title: "INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients presented with an intermediate form of Charcot-Marie-Tooth neuropathy as well as a glomerulopathy with FSGS on kidney biopsy."
explanation: Biopsy as the basis of the renal diagnosis in the founding cohort.
animal_models:
- name: INF2 R218Q knock-in mouse
species: Mouse
genotype: Inf2 R218Q knock-in, heterozygous and homozygous; compared against Inf2 knockout
publication: PMID:39536114
description: >-
The model that settles gain versus loss of function in vivo. Neither the knockout nor the
point-mutant mouse has a spontaneous kidney or neurological phenotype, so the discrimination
comes from a puromycin aminonucleoside challenge: the R218Q mouse is susceptible to
glomerular disease and the knockout is not.
modeled_mechanisms:
- target: Loss of Facilitated Autoinhibition of INF2
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
Reproduces the de-repressed actin phenotype this node asserts, measured directly on the
cytoskeleton rather than inferred from disease.
limitations: >-
Two limits, and they run in different directions. R218Q is an FSGS-range allele, so the
model speaks to the shared molecular lesion rather than to the CMT-range variants this
entry is about - it has no reported neurological phenotype at all. And the phenotype is
not spontaneous: it requires a puromycin aminonucleoside challenge, so what the model
demonstrates is susceptibility rather than disease.
readouts:
- name: Cellular actin measurement
target: Loss of Facilitated Autoinhibition of INF2
direction: INCREASED
interpretation: >-
Direct measurement of the de-repressed actin assembly that this entry's central node
asserts.
evidence:
- reference: PMID:39536114
reference_title: "INF2 mutations cause kidney disease through a gain-of-function mechanism."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "Colocalization, coimmunoprecipitation analyses, and cellular actin measurements showed that INF2 R218Q confers a gain-of-function effect on the actin cytoskeleton."
explanation: >-
The measured gain-of-function effect on the actin cytoskeleton. Graded IN_VITRO, not
MODEL_ORGANISM, even though the paper's headline result is an in vivo mouse
comparison: all three assays this sentence summarises are cell-based. The
coimmunoprecipitation was done on cotransfected 293T cells, and the colocalization
and F-actin/G-actin measurements on cultured podocytes derived from the knock-in
mice. CLAUDE.md puts cultured cells under IN_VITRO whether the cells are human or
animal. The abstract sentence itself names no system, so the grade comes from the
methods rather than from the quoted text.
evidence:
- reference: PMID:39536114
reference_title: "INF2 mutations cause kidney disease through a gain-of-function mechanism."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "R218Q INF2 mice are susceptible to glomerular disease, in contrast to INF2 knockout mice."
explanation: >-
Why this model is informative for the node: it separates gain from loss of function,
which is the claim the node makes. The genotype is R218Q, an FSGS-range allele, so the
item is INDIRECT for a CMT entry.
- target: Podocyte Actin Cytoskeleton Disorganization
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: >-
Models the renal arm, and only under challenge. Adhesion and mitochondria-related pathways
were enriched in the challenged R218Q mice.
limitations: >-
Requires a puromycin aminonucleoside insult to manifest, so it models susceptibility to
podocyte injury rather than spontaneous podocytopathy. It models nothing on the nerve
side.
evidence:
- reference: PMID:39536114
reference_title: "INF2 mutations cause kidney disease through a gain-of-function mechanism."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "RNA expression analysis showed that adhesion and mitochondria-related pathways were enriched in the PAN-treated R218Q mice."
explanation: >-
The cellular pathways engaged in the challenged model, which is what makes the link to
the podocyte node more than nominal.
- target: Demyelination with Onion Bulbs and Secondary Axonal Loss
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
description: >-
Recorded as a negative because it is a substantive one. No INF2 mouse - knockout or point
mutant - has a reported neurological phenotype, so the nerve arm of this disorder has no
animal model at all.
limitations: >-
The allele modelled is FSGS-range, so its silence on nerve may reflect the allele rather
than a species difference; that is exactly what makes it uninformative rather than
reassuring. A CMT-range knock-in has not been reported.
evidence:
- reference: PMID:39536114
reference_title: "INF2 mutations cause kidney disease through a gain-of-function mechanism."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Despite established roles in multiple cellular processes, neither INF2 knockout mice nor mice with a disease-associated point mutation display an evident kidney or neurologic phenotype."
explanation: >-
The explicit statement that no neurological phenotype is evident in either genotype,
which is the basis for FAILS_TO_RECAPITULATE.
treatments:
- name: Kidney transplantation
description: >-
Renal replacement for the ESRD end of the renal arm, and the point at which knowing the
genotype changes the counselling rather than only the label. Genetic FSGS generally does
not recur in the graft, in contrast to FSGS without a confirmed genetic cause, and an INF2
family with 14 affected members reported four transplants without recurrence.
treatment_term:
preferred_term: kidney transplantation
term:
id: NCIT:C15265
label: Kidney Transplantation
therapeutic_modality: SURGERY
target_phenotypes:
- preferred_term: Stage 5 chronic kidney disease
term:
id: HP:0003774
label: Stage 5 chronic kidney disease
evidence:
- reference: PMID:29038887
reference_title: "Mutations in INF2 may be associated with renal histology other than focal segmental glomerulosclerosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Four members received a kidney transplant without disease recurrence."
explanation: >-
Direct observation of non-recurrence in transplanted INF2 patients, rather than an
extrapolation from genetic FSGS as a class.
- reference: PMID:27733133
reference_title: "Diagnosing FSGS without kidney biopsy - a novel INF2-mutation in a family with ESRD of unknown origin."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Whilst patients with FSGS without a confirmed genetic cause have a high recurrence rate in the transplanted organ, patients with a mutation generally exhibit no recurrence and have a good prognosis."
explanation: >-
The general rule the INF2 observation instantiates. Graded INDIRECT because it is a
statement about genetically caused FSGS as a class rather than about INF2 specifically.
notes: >-
Practical consequence recorded because it is easy to lose: at-risk relatives of an INF2
proband have to be genotyped before being considered as living donors.
- name: Proteasome inhibition
description: >-
Experimental and not established for this disease. Bortezomib restored nephrin and
ameliorated podocytopathy and FSGS in the INF2 R218Q knockin mouse, and the authors propose
proteasome inhibition as a therapeutic strategy for INF2-mediated FSGS. R218Q is an
FSGS-range allele, the work is entirely preclinical, and nothing addresses the neuropathy.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: bortezomib
term:
id: CHEBI:52717
label: bortezomib
therapeutic_modality: SMALL_MOLECULE
target_mechanisms:
- target: Dynein-Mediated Nephrin Mistrafficking and Proteasomal Degradation
description: >-
Blocks the terminal step of the nephrin degradation route rather than restoring INF2
regulation.
evidence:
- reference: PMID:39621430
reference_title: "Dynll1-PI31 Interaction Enhances Proteolysis Through the Proteasome, Representing a Novel Therapeutic Target for INF2-Related FSGS."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "Suppression of proteasome-mediated proteolysis with proteasome inhibitors is a new therapeutic strategy for inverted formin 2-mediated FSGS."
explanation: >-
The therapeutic proposal, from mouse data on an FSGS-range allele. INDIRECT for this
entry on both counts.
- name: Rehabilitation and orthotic management
description: >-
Standard supportive management of the CMT phenotype - physical therapy, ankle-foot
orthoses, and orthopaedic management of the foot deformity and spinal curve. Included
because it is what patients actually receive; no cited source reports outcomes in CMTDIE
specifically, so this record carries no evidence rather than a manufactured quote.
treatment_term:
preferred_term: physical therapy
term:
id: NCIT:C15302
label: Physical Therapy
therapeutic_modality: BEHAVIORAL
target_phenotypes:
- preferred_term: Distal muscle weakness
term:
id: HP:0002460
label: Distal muscle weakness
notes: >-
Deliberately uncited. The abstracts cached for this entry describe genetics, pathology and
renal outcome; none reports a rehabilitation outcome in INF2 neuropathy, and quoting a
general CMT management statement would attribute to this disease something not measured in
it.
discussions:
- discussion_id: inf2_organ_selectivity
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Why does the same INF2 diaphanous-inhibitory-domain variant produce isolated
glomerulosclerosis in one carrier and combined neuropathy plus glomerulosclerosis in a
relative?
attaches_to:
- pathophysiology#Loss of Facilitated Autoinhibition of INF2
- pathophysiology#Disruption of the INF2-MAL-CDC42 Pathway in Schwann Cells
rationale: >-
Part of this is now answered, and the answer is positional. Variants between residues 184
and 245 produce monogenic FSGS; variants between residues 57 and 184 produce the dual
CMT-plus-FSGS disease. So where in the diaphanous inhibitory domain the substitution falls
predicts which organs are involved, and a cell-biological correlate has been measured:
CMT/FSGS variants cause more prominent mitochondrial fragmentation and distribution change
than FSGS variants, and the difference tracks the severity of cytoskeletal disruption. The
dual phenotype looks like the more globally disruptive end of one gradient rather than a
separate mechanism.
What that does not explain is the intrafamilial variability, and it is worth being precise
about why. The c.451T>C allele lies in the CMT-range segment, yet it segregated as isolated
FSGS in some members of one family and as the dual phenotype in others. Position therefore
sets what an allele *can* produce and something else decides what it *does* - a modifier,
a threshold effect, or ascertainment. Nothing published identifies it, and the authors who
established the positional rule end by saying that tissue-specific pathways in the two
phenotypes still need clarifying.
evidence:
- reference: PMID:25943269
reference_title: "INF2 mutations associated with dominant inherited intermediate Charcot-Marie-Tooth neuropathy with focal segmental glomerulosclerosis in two Chinese patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The c.451 T>C mutant was responsible for both isolated FSGS and a dual phenotype of FSGS and neuropathy within one family."
explanation: >-
The observation that makes this a gap rather than a curiosity: one allele, one family,
two organ distributions.
- reference: PMID:37491439
reference_title: "Characterization of cytoskeletal and structural effects of INF2 variants causing glomerulopathy and neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Variants between residues 184 and 245 of INF2, an actin assembly factor, produce the monogenic FSGS phenotype. Meanwhile, variants between residues 57 and 184 cause a dual-faceted disease involving peripheral neurons and podocytes (Charcot-Marie-Tooth CMT/FSGS)."
explanation: >-
The positional rule, which is the part of this question that has an answer and which the
earlier version of this entry did not have.
- reference: PMID:37491439
reference_title: "Characterization of cytoskeletal and structural effects of INF2 variants causing glomerulopathy and neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Notably, CMT/FSGS variants caused more prominent changes in mitochondrial distribution and fragmentation than FSGS variants and these changes correlated with the severity of cytoskeletal disruption."
explanation: >-
A measured cell-biological difference between the two variant classes, which turns the
positional rule from a correlation into a gradient with a candidate substrate.
- reference: PMID:37491439
reference_title: "Characterization of cytoskeletal and structural effects of INF2 variants causing glomerulopathy and neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Further study is needed to clarify tissue-specific pathways and/or cellular functions implicated in FSGS and CMT phenotypes."
explanation: >-
The authors' own statement that the tissue selectivity is not resolved by their result,
which is why this stays a KNOWLEDGE_GAP rather than being closed.
- discussion_id: inf2_renal_penetrance
kind: OPEN_QUESTION
status: OPEN
prompt: >-
What fraction of INF2 neuropathy carriers develop clinically significant renal disease,
and does that fraction justify lifelong renal surveillance?
attaches_to:
- phenotypes#Focal Segmental Glomerulosclerosis
- phenotypes#Proteinuria
rationale: >-
Every published frequency estimate is unusable for this question because of how the
cohorts were assembled. The founding series genotyped patients selected for having CMT
*and* FSGS, so 100% renal involvement in it is a property of the inclusion criteria. The
one family ascertained neurologically had normal albumin and creatinine and at most mildly
raised urine protein into the ninth decade. What is missing is an unselected INF2
neuropathy cohort with prospective renal follow-up; until it exists the entry records
renal involvement as FREQUENT on published cases rather than as a penetrance figure.
evidence:
- reference: PMID:30680856
reference_title: "A cryptic splicing mutation in the INF2 gene causing Charcot-Marie-Tooth disease with minimal glomerular dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Plasma albumin and creatinine were normal in all four cases, and urine protein was normal in one case and mildly raised in three patients"
explanation: >-
The one neurologically ascertained family, whose renal findings are the counterweight to
the founding cohort's selection.
notes: >-
Naming: MONDO and OMIM call this dominant intermediate CMT type E; much of the primary
literature calls it INF2-related CMT or CMT with FSGS. The synonyms list carries all three
so the entry is findable under whichever the reader knows.
Scope against the existing knowledge base: kb/disorders/Focal_Segmental_Glomerulosclerosis
covers the renal disease as an entity and mentions INF2 among its causes. This entry is the
neuropathy, and it curates the renal arm only as far as it is part of the INF2 phenotype -
it does not restate FSGS pathophysiology.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: Charcot-Marie-Tooth Disease Dominant Intermediate E (INF2) · 2026-09-03T19:31:31Z · View source
De novo curation of INF2-related dominant intermediate CMT from primary literature plus one openscientist deep-research run. The entry is built around the diaphanous-inhibitory-domain restriction of the allele spectrum and a gain-of-function reading supported both biochemically (escape from CAP-KAc-actin inhibition) and in vivo (point-mutant mice susceptible to glomerular disease where knockouts are not). The deep-research run materially changed the entry: it supplied the disease-specific nerve-biopsy series establishing a Schwann cell actinopathy, the positional genotype-phenotype rule that partly answers the organ-selectivity gap, the nephrin/Dynll1/PI31 podocyte mechanism, and the transplant non-recurrence finding that is the entry's only management-changing item. The nephrin mechanism is graded INDIRECT throughout because it was established for R218Q, an FSGS-range allele outside this entry's CMT-range segment. Validated: schema, terms, 58/58 snippets, entity refs, causal targets, duplicate keys, enum values, qualifier terms.
Disease: Charcot-Marie-Tooth Disease Dominant Intermediate E MONDO ID: MONDO:0013758 | OMIM: #614455 | Category: Mendelian (autosomal dominant) Causal gene: INF2 (Inverted Formin 2), 14q32.33, HGNC:23791
Charcot-Marie-Tooth disease Dominant Intermediate E (CMTDIE) is a rare autosomal-dominant Mendelian disorder that uniquely couples an intermediate-type peripheral neuropathy with focal segmental glomerulosclerosis (FSGS) of the kidney. It is caused by heterozygous mutations in INF2, a gene encoding an endoplasmic-reticulum–anchored, actin-nucleating formin. Pathogenic variants cluster tightly in the diaphanous-inhibitory domain (DID) encoded by exons 2–4. In a landmark cohort, 12 of 16 (75%) patients with CMT plus glomerulopathy carried DID mutations, establishing INF2 as the dominant cause of the dual phenotype (PMID: 22187985).
The mechanism is a gain-of-function actinopathy, not haploinsufficiency: point-mutant Inf2 knock-in mice develop glomerular disease while Inf2 knockouts do not (PMID: 39536114). Loss of the DID-mediated autoinhibition produces excessive/dysregulated actin polymerization that injures two highly polarized cell types simultaneously: Schwann cells, producing a "Schwann-cell actinopathy" with demyelinating-plus-axonal features and intermediate nerve conduction velocities (PMID: 24487800), and podocytes, producing FSGS via dysregulated dynein-mediated trafficking of nephrin to the proteasome, abnormal mitochondrial dynamics, and terminal MRTF/SRF- and p53-driven cell death (PMID: 39621430, PMID: 39586895).
There is a positional genotype-phenotype gradient along the DID: N-terminal residues (57–184) produce the dual CMT/FSGS phenotype, whereas more C-terminal residues (184–245) tend to produce isolated FSGS (PMID: 37491439). Renal disease is progressive, frequently reaching end-stage renal disease (ESRD) in the third-to-fourth decade, but—importantly for counseling—genetic (INF2) FSGS does not recur after kidney transplantation, unlike idiopathic FSGS (PMID: 27733133). No disease-specific therapy exists; management is supportive, though proteasome inhibition and allele-selective silencing are promising experimental strategies.
Overview. CMTDIE is a hereditary neurologic-renal syndrome in which an intermediate form of Charcot-Marie-Tooth peripheral neuropathy co-occurs with steroid-resistant FSGS. "Intermediate" refers to nerve conduction velocities that fall between the demyelinating (CMT1, <38 m/s) and axonal (CMT2, >45 m/s) ranges, reflecting mixed demyelinating and axonal pathology. The disease is distinctive among the CMTs because the same mutation damages both the peripheral nervous system and the kidney glomerulus.
Key identifiers.
| Resource | Identifier |
|---|---|
| MONDO | MONDO:0013758 |
| OMIM | #614455 (Charcot-Marie-Tooth disease, dominant intermediate E) |
| Gene | INF2, OMIM *610982, HGNC:23791, 14q32.33 |
| ICD-10 | G60.0 (Hereditary motor and sensory neuropathy) |
| MeSH | Charcot-Marie-Tooth Disease (D002607) |
| Orphanet | Related entry: Charcot-Marie-Tooth disease with glomerulopathy |
Synonyms / alternative names. CMTDIE; Dominant intermediate Charcot-Marie-Tooth disease type E (DI-CMTE); CMT–FSGS; INF2-related CMT with glomerulopathy; hereditary neuropathy with glomerulopathy.
Information source. The knowledge base is derived from aggregated disease-level resources (OMIM, ClinVar) plus individual-patient case series and family pedigrees reported in the primary literature. There is no large EHR-derived cohort; the disease is rare, and knowledge rests on multi-generation families and small case series.
Primary cause — genetic. CMTDIE is a monogenic disorder caused by heterozygous mutations in INF2. In the defining cohort, Boyer et al. genotyped 16 index patients with CMT plus FSGS who lacked PMP22/MPZ mutations and identified nine novel heterozygous INF2 mutations in 12/16 (75%), all in exons 2–3 encoding the DID (PMID: 22187985). Inheritance is autosomal dominant; de novo mutations also occur and may be relatively common in the dual phenotype (PMID: 24174593).
Genetic risk factors. The causal variants are the DID missense/in-frame variants themselves. The position of the variant is the principal modifier of the phenotype (see Section 4). No independent susceptibility loci or GWAS signals are described—this is a Mendelian, not complex, disease.
Environmental risk factors. None established as causative. CMTDIE is fully determined by the germline INF2 variant. However, experimental models show that a "second hit" of glomerular stress unmasks the renal phenotype: R218Q knock-in mice are normal at baseline but develop proteinuria/FSGS after puromycin aminonucleoside (PAN) or protamine sulfate injury (PMID: 38915495, PMID: 27350175). This implies that mutant INF2 confers a susceptibility to injury rather than causing spontaneous glomerular destruction, and that podocyte stressors could plausibly modulate human disease onset—though this is inferred from models, not demonstrated clinically.
Protective factors. No genetic or environmental protective factors are established. The observation that INF2 knockout does not cause disease implies that reducing mutant allele expression (allele-selective silencing) would be protective—a therapeutic hypothesis, not a natural protective factor.
Gene-environment interactions. Not characterized in humans. The model data (mutation + injury synergy) are the closest analog.
CMTDIE has two organ-system phenotype clusters: neurologic and renal, plus occasional additional features.
| Phenotype | Type | HPO term | Onset | Severity/Progression |
|---|---|---|---|---|
| Distal muscle weakness (legs > arms) | Clinical sign | HP:0009053 (distal lower limb amyotrophy) | Childhood–adolescence (mean onset ~11.5 y) | Slowly progressive |
| Peripheral sensory loss | Symptom | HP:0106487 | Childhood–adult | Progressive |
| Pes cavus | Physical manifestation | HP:0001761 | Childhood | Stable/progressive |
| Distal muscle atrophy | Clinical sign | HP:0003693 | Adolescence | Progressive |
| Kyphoscoliosis | Physical manifestation | HP:0002751 | Variable | Variable |
| Intermediate nerve conduction velocity | Laboratory/electrophysiology | HP:0030181 (variable NCV) | Detectable at diagnosis | Stable trait |
Case reports document mean CMT onset ~11.5 years (range 3–17) with slowly progressive sensorimotor polyneuropathy, pes cavus, and kyphoscoliosis (PMID: 30680856). Rare families show additional CNS features (intellectual disability, more severe sensorineural hearing loss) (PMID: 24174593) or transient speech difficulty (PMID: 25943269).
| Phenotype | Type | HPO term | Onset | Severity/Progression |
|---|---|---|---|---|
| Focal segmental glomerulosclerosis | Pathology/lab | HP:0000097 | Childhood–adulthood | Progressive to ESRD |
| Proteinuria | Laboratory abnormality | HP:0000093 | Childhood–adult | Progressive |
| Nephrotic syndrome | Clinical | HP:0000100 | Variable | Steroid-resistant |
| End-stage renal disease | Clinical | HP:0003774 | 3rd–4th decade typically | Terminal renal outcome |
Renal involvement ranges from minimal proteinuria to steroid-resistant nephrotic syndrome progressing to ESRD. Some INF2 mutations produce isolated CMT with minimal/absent kidney involvement (PMID: 30680856), and INF2 can present with non-FSGS histology (minimal-change glomerulopathy, IgA nephropathy) within the same family (PMID: 29038887).
Quality-of-life impact. The combination is doubly disabling: progressive distal weakness impairs gait and manual dexterity (requiring orthoses), while progression to ESRD imposes dialysis dependence or transplantation. No formal EQ-5D/SF-36 data specific to CMTDIE are published.
Frequency note. Within INF2-mutation carriers, both variable penetrance and intrafamilial variability are documented—the same variant can produce isolated FSGS in one relative and the full dual phenotype in another (PMID: 25943269).
Causal gene. INF2 (Inverted Formin 2), 14q32.33, HGNC:23791, OMIM *610982. INF2 is a member of the diaphanous-related formin family that nucleates and elongates actin filaments and also regulates microtubule dynamics.
Pathogenic variants. - Domain clustering: Nearly all CMTDIE variants localize to the diaphanous-inhibitory domain (DID) encoded by exons 2–4. Boyer et al. found all nine mutations in exons 2–3 (PMID: 22187985). - Variant type: Predominantly missense (e.g., p.L77P, p.L128P, p.G114D, p.L132P, p.G73D, p.V108D), with some in-frame deletions (p.Leu69_Ser72del) and cryptic splice variants (c.271C>G producing p.Arg91_Gln130del) (PMID: 22961558, PMID: 24174593, PMID: 24750328, PMID: 30680856). - Classification: Pathogenic/likely pathogenic per ACMG (segregation with disease, absence in controls, functional data). Variants are typically germline; de novo events documented. - Allele frequency: Essentially absent from population databases (gnomAD)—consistent with a rare, penetrant, dominant disorder. - Functional consequence: Gain-of-function / dominant-negative on actin regulation (see below), NOT loss-of-function.
Positional genotype-phenotype correlation. Ueda et al. showed that variants between residues 184 and 245 produce isolated (monogenic) FSGS, while variants between residues 57 and 184 cause the dual CMT/FSGS phenotype (PMID: 37491439). The paper states: "Variants between residues 184 and 245 of INF2, an actin assembly factor, produce the monogenic FSGS phenotype. Meanwhile, variants between residues 57 and 184 cause a dual-faceted disease involving peripheral neurons and podocytes." Mechanistically, CMT/FSGS variants (G73D, V108D) caused more severe cytoskeletal disruption and mitochondrial fragmentation than FSGS-only variants (T161N, N202S), providing a molecular basis for why the more N-terminal variants add the neuropathy.
Gain-of-function evidence. Subramanian et al. demonstrated that the R218Q point mutation, but not the knockout allele, confers susceptibility to glomerular disease in mice — "R218Q INF2 mice are susceptible to glomerular disease, in contrast to INF2 knockout mice" — and cellular assays showed the mutation alters the actin cytoskeleton via a gain-of-function effect (PMID: 39536114, PMID: 38915495). Labat-de-Hoz et al. summarize: "These mutations disrupt INF2 regulation, leading to excessive actin polymerization" (PMID: 39586895).
Modifier genes / epigenetics / chromosomal abnormalities. The variant position is the dominant modifier. No specific modifier genes, disease-specific epigenetic marks, or chromosomal abnormalities are established for CMTDIE.
Gene/GO annotations. INF2 — GO:0007015 (actin filament organization), GO:0051017 (actin filament bundle assembly), GO:0000266 (mitochondrial fission), GO:0032956 (regulation of actin cytoskeleton organization). Cellular component: GO:0005783 (endoplasmic reticulum), GO:0005884 (actin filament).
CMTDIE is a monogenic disease with no established environmental cause. There are no implicated toxins, radiation, pollution, occupational exposures, lifestyle factors, or infectious agents. The only environmental dimension is experimental: in mouse models, superimposed glomerular injury (PAN, protamine sulfate) is required to unmask the renal phenotype in R218Q knock-in animals (PMID: 38915495, PMID: 27350175), suggesting—by inference—that podocyte stressors may modulate onset in humans. Standard nephroprotective avoidance of nephrotoxins is prudent but not disease-specific.
1. Heterozygous missense/in-frame mutation in INF2 DID (exons 2–4)
│ leads to
2. Loss of DID-mediated autoinhibition of INF2 (normally held inactive by a
CAP1 / lysine-acetylated-actin complex bound to the DID)
│ results in
3. Constitutive / dysregulated INF2 activity → EXCESSIVE ACTIN POLYMERIZATION
(gain-of-function; NOT haploinsufficiency)
│
├──────────── BRANCH A: SCHWANN CELL (peripheral nerve) ────────────┐
│ 4a. Perturbation of the INF2–MAL–CDC42 myelination pathway │
│ leads to │
│ 5a. Global disruption of the Schwann-cell actin cytoskeleton; │
│ abnormal β-actin accumulation in Schwann cell cytoplasm │
│ results in │
│ 6a. Chronic demyelination/remyelination + progressive axonal loss │
│ → intermediate nerve conduction velocities │
│ → CMT phenotype (distal weakness, atrophy, pes cavus) │
│ │
└──────────── BRANCH B: PODOCYTE (kidney glomerulus) ────────────────┘
4b. Disrupted INF2 sequestration of Dynll1 → Dynll1 captured by PI31
leads to
5b. Dynein-mediated transport of nephrin to the proteasome →
proteasome-mediated nephrin degradation → slit-diaphragm loss
(in parallel) abnormal mitochondrial fission/adhesion defects
results in
6b. Foot-process effacement, proteinuria → FSGS → ESRD (3rd–4th decade)
7. CONVERGENT TERMINAL STEP (both cell types): excess F-actin drives MRTF/SRF
transcriptional reprogramming + abnormal mitochondrial dynamics →
mitotic abnormalities → p53-mediated cell death → cell loss
Steps 1–3 and the podocyte branch (4b–6b) are experimentally demonstrated; the Schwann-cell branch (4a–6a) is supported by human nerve pathology and INF2–MAL interaction data but the in-vivo chain in nerve is partly inferred. Step 7 is drawn from cell-biology/review synthesis.
Molecular pathways. The central lesion is dysregulated actin polymerization by an ER-anchored formin. In Schwann cells, INF2 acts through the INF2–MAL–CDC42 pathway; Boyer et al. showed "INF2 colocalizes and interacts with MAL in Schwann cells. The INF2 mutants perturbed the INF2-MAL-CDC42 pathway" (PMID: 22187985). Downstream, excess G-/F-actin signaling engages the MRTF/SRF transcriptional axis (PMID: 39586895). INF2 is normally activated physiologically through "calmodulin binding, KAc-actin deacetylation, G-actin binding, or association with the Cdc42 GTPase" — regulatory inputs bypassed by DID mutations.
Cellular processes. Dysregulated actin dynamics, defective intracellular/vesicular trafficking, abnormal mitochondrial fission and fusion (INF2 nucleates actin at ER–mitochondria contact sites to drive DRP1-mediated fission), impaired cell adhesion, and ultimately p53-mediated cell death (PMID: 39586895, PMID: 39184068, PMID: 39774009).
Protein dysfunction. DID mutations abolish the DID–DAD (diaphanous autoregulatory domain) autoinhibitory clamp, releasing the FH2 domain to over-nucleate actin. This is a gain-of-function/dominant mechanism, definitively shown because point mutants but not knockouts cause disease (PMID: 39536114).
Metabolic / mitochondrial changes. Mutant INF2 causes abnormal mitochondrial dynamics and fragmentation; CMT/FSGS variants produce more severe mitochondrial fragmentation than FSGS-only variants (PMID: 37491439). Mitochondrial-associated ER membrane (MAM) actin dynamics are implicated in podocyte injury (PMID: 41864363).
Tissue damage mechanisms. Schwann cell: Mathis et al. examined six CMTDIE nerve biopsies and reported that "these lesions reflect a global disorder of the actin cytoskeleton in Schwann cells and that CMTDIE is the first peripheral nerve disorder associated with a Schwann cell actinopathy," including "abnormal accumulation of β-actin in the cytoplasm of Schwann cells" (PMID: 24487800). Podocyte: nephrin proteostasis failure and foot-process effacement.
Biochemical abnormality (podocyte, druggable node). Sun et al. and Williquett et al. defined the mechanism: "The R218Q mutation in INF2 disrupted sequestration of Dynll1 by INF2, allowing Dynll1 to be captured by PI31 and promoting dynein-mediated transport of nephrin to the proteasome" (PMID: 33443052, PMID: 39621430). Proteasome inhibition (bortezomib) or knockdown of PI31/Dynll1 restored nephrin proteostasis and protected R218Q mice against PAN-induced FSGS.
Terminal transcriptional / cell-death cascade. Labat-de-Hoz et al. describe how excess actin causes "altered intracellular trafficking, abnormal mitochondrial dynamics, and profound transcriptional reprogramming via the MRTF/SRF complex, resulting in mitotic abnormalities and p53-mediated cell death" (PMID: 39586895).
Cell types (CL terms): Schwann cell (CL:0002573), podocyte (CL:0000653). Anatomy (UBERON): peripheral nerve (UBERON:0000044), renal glomerulus (UBERON:0000074). GO biological processes: GO:0007015 (actin filament organization), GO:0000266 (mitochondrial fission), GO:0006511 (ubiquitin-dependent protein catabolic process).
Organ level. - Primary: Peripheral nervous system (peripheral nerves; UBERON:0000044) and kidney (renal glomerulus; UBERON:0000074). - Body systems: Nervous system (peripheral) and urinary/renal system. - Secondary: Skeletal deformities secondary to neuropathy (pes cavus, kyphoscoliosis); ESRD complications (cardiovascular, anemia, mineral-bone disease).
Tissue and cell level. - Nervous tissue: myelinating Schwann cells (CL:0002573) — the principal cellular target in nerve; secondary axonal loss. - Renal tissue: glomerular visceral epithelial cells (podocytes, CL:0000653) — the principal renal target; the slit diaphragm (nephrin/podocin) is the molecular casualty.
Subcellular level (GO cellular component). Endoplasmic reticulum (GO:0005783, where ER-anchored INF2 resides), actin cytoskeleton (GO:0015629), mitochondrion (GO:0005739, abnormal fission/fusion), proteasome complex (GO:0000502, nephrin degradation), ER–mitochondria contact site / MAM.
Localization / lateralization. Neuropathy is bilateral, symmetric, length-dependent (distal legs first). Renal involvement is bilateral (systemic glomerular disease).
Onset. Neuropathy typically begins in childhood to adolescence (mean CMT onset ~11.5 years, range 3–17) with insidious, slowly progressive distal weakness (PMID: 30680856). Renal onset is variable, ranging from childhood to adulthood (PMID: 23014460).
Progression. Both components are chronic and progressive. Neuropathy progresses slowly over decades. Renal disease progresses from proteinuria to nephrotic syndrome to FSGS: Barua et al. report that "INF2-related disease showed variable penetrance, with onset of disease ranging widely from childhood to adulthood, and commonly leading to end-stage renal disease in the third and fourth decade of life" (PMID: 23014460). Renal dysfunction is more severe and earlier-onset when neuropathy coexists (PMID: 24174593).
Patterns. No spontaneous remission. Disease is lifelong. The window for renal intervention is before advanced glomerulosclerosis; the theoretical critical period for any future INF2-directed therapy would be prior to irreversible podocyte loss.
Epidemiology. CMTDIE is rare (no precise prevalence; part of the broader CMT spectrum affecting ~1 in 2,500). Among autosomal-dominant familial FSGS, INF2 mutations explain ~9%: Barua et al. found "Mutations in INF2 were found in a total of 20 of the 215 families... thereby explaining disease in 9%" versus only 2/281 sporadic cases (PMID: 23014460). By comparison, ACTN4 accounted for ~3% and TRPC6 ~2%.
Inheritance genetics. - Pattern: Autosomal dominant; de novo mutations documented (PMID: 24174593). - Penetrance: Variable/incomplete — "variable penetrance, with onset ranging widely from childhood to adulthood" (PMID: 23014460). - Expressivity: Variable, including intrafamilial variability where the same variant causes isolated FSGS in one relative and dual CMT/FSGS in another (PMID: 25943269). - Anticipation, mosaicism, founder effects, consanguinity: Not established (dominant, non-repeat-expansion disease; consanguinity not relevant).
Population demographics. Reported across diverse populations—European, Korean (PMID: 24750328), Chinese (PMID: 25943269, PMID: 31515790)—with no ethnic predilection. No strong sex bias reported for the Mendelian disease.
Clinical tests. - Electrophysiology (key): Nerve conduction studies show intermediate motor NCV with both demyelinating and axonal features—the diagnostic signature (PMID: 24750328). - Urinalysis / renal labs: Proteinuria screening is essential in every CMT patient — "we strongly suggest to screen for proteinuria in CMT patients, in order to identify patients with this renal-neurologic phenotype in an early stage" (PMID: 25439738). Serum albumin, creatinine, eGFR track renal function. - Nerve biopsy (sural): Chronic demyelination/remyelination, progressive axonal loss, whorl-like Schwann-cell proliferations, abnormal β-actin accumulation — a Schwann-cell actinopathy (PMID: 24487800). - Renal biopsy: FSGS (or occasionally minimal-change/IgA histology) (PMID: 29038887).
Genetic testing (definitive). Targeted single-gene INF2 sequencing (exons 2–4) or CMT/FSGS gene panels; whole-exome sequencing has identified novel variants (e.g., p.L132P) (PMID: 24750328). Screening should not be restricted to patients with combined neuro-renal disease, since INF2 variants can cause isolated CMT (PMID: 30680856) or isolated FSGS. INF2 testing is strongly recommended in any patient with CMT plus early nephropathy (PMID: 24174593). Diagnosis via genetics can sometimes obviate renal biopsy (PMID: 27733133).
Clinical criteria / differential diagnosis. Differentiate from other intermediate CMTs (CMT1X/GJB1, DI-CMT from DNM2, YARS), CMT1A (PMP22 duplication), and isolated genetic FSGS (NPHS2, TRPC6, ACTN4, WT1). The combination of intermediate NCV plus proteinuria/FSGS strongly points to INF2.
Screening. Cascade genetic testing of at-risk relatives; urine protein screening in known carriers. No newborn screening exists.
Renal outcome. Progressive to ESRD, "commonly leading to end-stage renal disease in the third and fourth decade of life" (PMID: 23014460). Renal disease is generally steroid-resistant.
Key transplant prognostic distinction. Genetic (INF2) FSGS does not recur after kidney transplantation, in sharp contrast to idiopathic FSGS: "Whilst patients with FSGS without a confirmed genetic cause have a high recurrence rate in the transplanted organ, patients with a mutation generally exhibit no recurrence and have a good prognosis" (PMID: 27733133). Direct clinical confirmation: in an INF2 family with 14 affected members, "Four members received a kidney transplant without disease recurrence" (PMID: 29038887). This is a major counseling anchor—transplantation offers durable renal replacement.
Neurologic outcome. Slowly progressive disability from distal weakness, atrophy, and foot deformity; not typically life-limiting on its own. Life expectancy is governed largely by renal outcome and transplant success.
Prognostic factors. Variant position (dual vs isolated phenotype), age at renal onset, degree of proteinuria/glomerulosclerosis at diagnosis.
No disease-specific/curative therapy currently exists. Management is supportive and organ-directed.
Neurologic / supportive-rehabilitative. - Physical therapy, occupational therapy, ankle-foot orthoses, orthopedic management of pes cavus/kyphoscoliosis (NCIT: Physical Therapy, Orthotic Device). Symptomatic pain management as needed.
Renal. - RAAS blockade (ACE inhibitors/ARBs) for proteinuria (antiproteinuric, nephroprotective; NCIT: ACE Inhibitor, Angiotensin Receptor Antagonist). FSGS here is generally steroid-resistant, so immunosuppression is of limited value. - Renal replacement: dialysis and kidney transplantation (NCIT: Kidney Transplantation)—the latter with excellent, non-recurring outcomes (PMID: 27733133).
Experimental / emerging (mechanism-directed). - Proteasome inhibition: Bortezomib restored nephrin proteostasis and protected R218Q mice — "Suppression of proteasome-mediated proteolysis with proteasome inhibitors is a new therapeutic strategy for inverted formin 2-mediated FSGS" (PMID: 39621430). Targeting the PI31–Dynll1 interaction is a proposed node. - Allele-selective silencing (ASO/siRNA): Because knockout is non-pathogenic while the point mutant is, selectively silencing the mutant allele is a rational (untested-in-human) strategy. - No pharmacogenomic, gene-therapy, cell-therapy, or immunotherapy protocols are established for CMTDIE.
Treatment strategy. Genotype-guided: confirm INF2 variant, monitor proteinuria and nerve function, initiate RAAS blockade early, plan for transplantation, and counsel on non-recurrence.
Primary prevention. Not possible for a germline Mendelian disorder. Genetic counseling is central: autosomal dominant inheritance means 50% transmission risk; prenatal diagnosis and preimplantation genetic diagnosis (PGD) are options for known family variants.
Secondary prevention. Cascade genetic testing of at-risk relatives and proteinuria screening in carriers enables early detection and early RAAS blockade to slow renal progression (PMID: 25439738).
Tertiary prevention. Nephroprotection (blood-pressure control, avoidance of nephrotoxins), management of ESRD complications, orthopedic/rehabilitative care to preserve mobility, and timely transplantation.
Immunization / public health / environmental interventions. Not applicable (non-infectious, non-environmental).
Mouse models (principal).
| Model | Type | Key finding | PMID |
|---|---|---|---|
| Inf2 R218Q knock-in | Point-mutant knock-in | Susceptible to PAN-induced proteinuria/FSGS; demonstrates gain-of-function | 39536114, 38915495 |
| Inf2 knockout | Null allele | Minimal renal phenotype — does NOT recapitulate disease | 39536114 |
| Inf2 R218Q knock-in (protamine) | Injury model | Impaired podocyte/slit-diaphragm recovery; nephrin/podocin mislocalization | 27350175 |
| Patient iPSC kidney organoid (S186P) | In vitro human | Recapitulates defective adhesion and mitochondrial phenotypes | 38915495 |
Phenotype recapitulation. The R218Q knock-in reproduces the renal phenotype (only after a second-hit injury) and demonstrates the gain-of-function mechanism and the therapeutic tractability of proteasome inhibition. Human iPSC-derived podocyte organoids recapitulate the adhesion/mitochondrial defects.
Model limitations. (1) The neuropathy component is poorly modeled—published mouse work focuses on kidney, not Schwann-cell disease. (2) Baseline mice are near-normal; a stressor is required to unmask renal disease, so the models capture susceptibility rather than spontaneous progressive FSGS. (3) The positional genotype-phenotype gradient (why some variants add neuropathy) is not fully reconstructed in vivo.
Resources: MGI (mouse Inf2), patient-derived iPSC/organoid lines.
CMTDIE is best understood as a single molecular lesion producing a two-organ actinopathy. A DID mutation releases INF2 from autoinhibition, and the resulting excess/dysregulated actin polymerization is simultaneously toxic to the two most architecturally demanding cell types in the body—myelinating Schwann cells and podocytes—both of which depend on exquisitely controlled actin cytoskeletons for their elaborate membrane processes (myelin wraps; foot processes/slit diaphragm).
INF2 DID mutation (gain-of-function)
│
excess/dysregulated actin polymerization
│
┌──────────────┴───────────────┐
SCHWANN CELL PODOCYTE
(INF2–MAL–CDC42 (Dynll1→PI31→dynein→
pathway perturbed; proteasomal nephrin loss;
β-actin accumulation) mitochondrial/adhesion defects)
│ │
demyelination + foot-process effacement
axonal loss → FSGS
│ │
intermediate-NCV proteinuria → ESRD
neuropathy (3rd–4th decade)
└──────────┬────────────────┘
MRTF/SRF reprogramming + abnormal
mitochondrial dynamics + p53 cell death
(convergent terminal cell-loss step)
The positional gradient (residues 57–184 → dual; 184–245 → renal-only) implies that the N-terminal DID region governs an interaction (plausibly the Schwann-cell INF2–MAL–CDC42 axis) whose disruption is required to add neuropathy, whereas podocyte injury is triggered across a broader mutational span. The gain-of-function nature reframes therapy: rather than replacing lost function, the goal is to reduce aberrant activity—hence the appeal of allele-selective silencing (mimicking the benign knockout) and downstream proteasome inhibition (rescuing nephrin).
| PMID | Title (abbrev.) | Contribution |
|---|---|---|
| 22187985 | INF2 mutations in CMT with glomerulopathy | Establishes INF2 DID as cause in 75% of CMT+FSGS; INF2–MAL–CDC42 in Schwann cells |
| 37491439 | Cytoskeletal/structural effects of INF2 variants | Positional genotype-phenotype gradient (57–184 dual; 184–245 renal-only) |
| 39536114 | INF2 causes kidney disease through gain-of-function | Point-mutant but not knockout causes disease → gain-of-function |
| 38915495 | Missense mutant gain-of-function INF2-FSGS | R218Q knock-in + organoid recapitulate adhesion/mitochondrial defects |
| 24487800 | Neuropathology: Schwann cell actinopathy | Defines nerve pathology as Schwann-cell actinopathy; β-actin accumulation |
| 23014460 | INF2 in familial vs sporadic FSGS | INF2 = 9% of AD familial FSGS; variable penetrance; ESRD in 3rd–4th decade |
| 33443052 | Dysregulated dynein trafficking of nephrin | Podocyte mechanism: nephrin mistrafficking |
| 39621430 | Dynll1-PI31 / proteasome target | Dynll1→PI31→proteasomal nephrin loss; proteasome inhibition therapeutic |
| 39586895 | Regulation of INF2 in inherited disorders | Excess actin → MRTF/SRF + p53 cell death; physiological activators |
| 27733133 | Diagnosing FSGS without biopsy | Genetic FSGS does not recur post-transplant |
| 29038887 | INF2 with non-FSGS histology | 4 transplants without recurrence; histologic heterogeneity |
| 30680856 | Cryptic splice INF2, minimal renal | INF2 can cause isolated CMT; expands testing indications |
| 24174593 | De novo INF2 mutations | De novo events; broader phenotype (ID, hearing loss) |
| 25439738 | CMT: are you testing for proteinuria? | Clinical mandate to screen CMT patients for proteinuria |
Evidence source types: Human clinical/genetic (case series, pedigrees, cohort genotyping); model organism (R218Q knock-in and knockout mice); in vitro (patient iPSC organoids, cultured podocytes); computational/structural (variant modeling).
Report compiled from 8 confirmed findings and 27 reviewed papers across 5 investigation iterations. Ontology suggestions: MONDO:0013758; genes/GO: INF2 (GO:0007015, GO:0000266, GO:0005783); cells CL:0002573 (Schwann cell), CL:0000653 (podocyte); anatomy UBERON:0000044 (peripheral nerve), UBERON:0000074 (renal glomerulus); phenotypes HP:0000097 (FSGS), HP:0000093 (proteinuria), HP:0001761 (pes cavus), HP:0003774 (ESRD).
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 22 |
| Resolved | 22 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 2 |
| Quoted claims found in source | 1 |
| Quoted claims not found in source | 1 |
| References weighed for topical relevance | 22 |
| On topic | 19 |
| Off topic | 0 |
Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:
Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.
PMID:23014460 (abstract only): "variable penetrance, with onset ranging widely from childhood to adulthood"Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 26 |
| Resolved | 24 |
| Unresolved (possible confabulation) | 1 |
| Obsolete | 0 |
| Unverifiable | 1 |
| Terms whose name was checked | 21 |
| Terms named correctly | 9 |
| Terms named as a different term | 11 |
| Terms whose name is worth a second look | 1 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0013758 (3 mentions) - the report calls it "MONDO"; MONDO calls it Charcot-Marie-Tooth disease dominant intermediate EHP:0001761 (2 mentions) - the report calls it "Physical manifestation", "pes cavus"; HP calls it Pes cavusHP:0003693 (1 mention) - the report calls it "Clinical sign"; HP calls it Distal amyotrophyHP:0002751 (1 mention) - the report calls it "Physical manifestation"; HP calls it KyphoscoliosisHP:0030181 (1 mention) - the report calls it "variable NCV"; HP calls it Gordon reflexHP:0000097 (2 mentions) - the report calls it "Pathology/lab", "FSGS"; HP calls it Focal segmental glomerulosclerosisHP:0000093 (2 mentions) - the report calls it "Laboratory abnormality", "proteinuria"; HP calls it ProteinuriaHP:0000100 (1 mention) - the report calls it "Clinical"; HP calls it Nephrotic syndromeHP:0003774 (2 mentions) - the report calls it "Clinical", "ESRD"; HP calls it Stage 5 chronic kidney diseaseCL:0002573 (3 mentions) - the report calls it "Schwann cells", "Nervous tissue: myelinating Schwann cells", "Schwann cell"; CL calls it Schwann cellUBERON:0000044 (3 mentions) - the report calls it "peripheral nerve"; UBERON calls it dorsal root ganglionThese identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:
HP:0106487 (1 mention), reported as "Symptom" - HP does not contain this termThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0009053 (1 mention) - the report calls it "distal lower limb amyotrophy"; HP calls it Distal lower limb muscle weaknessThe report gives these identifiers more than one name of its own:
HP:0001761 - called "Physical manifestation", "pes cavus"HP:0000097 - called "Pathology/lab", "FSGS"HP:0000093 - called "Laboratory abnormality", "proteinuria"HP:0003774 - called "Clinical", "ESRD"CL:0002573 - called "Schwann cells", "Nervous tissue: myelinating Schwann cells", "Schwann cell"